DESCRIPTION: The focus of this application is on the role of the calpains in diabetic neuropathy. The general hypothesis to be tested is that the calpain/calpastatin system plays a pivotal role in the pathogenesis of axonal degenerations. Specific aim 1 is to identify and measure changes in the calpain/calpastatin system during Wallerian degeneration, using specific antibodies and in vitro protease assays. Specific aim 2 is to test the potential for calpain inhibition to modify the neuropathological changes induced in dorsal root ganglion explant cultures by hyperglycemia. The third specific aim is to test the ability of various permeant calpain inhibitors to prevent or reduce neuropathy in streptozotocin-induced rat diabetic neuropathy